RESUMEN
To assess the reliability of electron beam computed tomography (EBCT), measurements of single-kidney renal blood flow (RBF), glomerular filtration rate (GFR), and intratubular contrast medium concentration (ITC) of radiographic contrast media were quantified in anesthetized pigs before and after acetylcholine-induced vasodilation and diuresis. EBCT measurements were compared with those obtained with intravascular Doppler and inulin clearance. The capability of EBCT to detect chronic changes in single-kidney function was evaluated in pigs with unilateral renal artery stenosis, and their long-term reproducibility in normal pigs was studied repeatedly at 1-mo intervals. EBCT-RBF (ml/min) correlated with Doppler-RBF as RBF(EBCT) = 45 + 1.07 * RBF(Doppler), r = 0.81. EBCT-GFR (ml/min) correlated with inulin clearance as GFR(EBCT) = 11.7 + 1.02 * GFR(inulin), r = 0.80. During vasodilation, RBF and GFR increased, whereas ITC decreased along the nephron. In renal artery stenosis, single-kidney GFR decreased linearly with the degree of stenosis, and ITC increased along the nephron, indicating increased fluid reabsorption. EBCT-RBF, GFR, and ITC were similar among repeated measurements. This approach might be invaluable for simultaneous quantification of regional hemodynamics and function in the intact kidneys, in a manner potentially applicable to humans.
Asunto(s)
Tasa de Filtración Glomerular/fisiología , Túbulos Renales/fisiología , Obstrucción de la Arteria Renal/diagnóstico por imagen , Circulación Renal/fisiología , Tomografía Computarizada por Rayos X , Animales , Femenino , Inulina/farmacocinética , Riñón/irrigación sanguínea , Riñón/diagnóstico por imagen , Riñón/fisiología , Flujometría por Láser-Doppler , Reproducibilidad de los Resultados , PorcinosRESUMEN
The pathophysiological mechanisms responsible for maintenance of chronic renovascular hypertension remain undefined. Excess angiotensin II generation may lead to release of reactive oxygen species and increased vasoconstrictor activity. To examine the potential involvement of oxidation-sensitive mechanisms in the pathophysiology of renovascular hypertension, blood samples were collected and renal blood flow measured with electron-beam computed tomography in pigs 5 and 10 weeks after induction of unilateral renal artery stenosis (n=7) or sham operation (n=7). Five weeks after procedure, plasma renin activity and mean arterial pressure were elevated in hypertensive pigs. Levels of prostaglandin F2alpha (PGF(2alpha))-isoprostanes, vasoconstrictors and markers of oxidative stress, also were significantly increased (157+/-21 versus 99+/-16 pg/mL; P<0.05) and correlated with both plasma renin activity (r=0.83) and arterial pressure (r=0.82). By 10 weeks, plasma renin activity returned to baseline but arterial pressure remained elevated (144+/-10 versus 115+/-5 mm Hg; P:<0.05). Isoprostane levels remained high and still correlated directly with the increase in arterial pressure (r=0.7) but not with plasma renin activity. Stenotic kidney blood flow was decreased at both studies. In shock-frozen cortical tissue, ex vivo endogenous intracellular radical scavengers were significantly decreased in both kidneys. The present study demonstrates, for the first time, that in early renovascular hypertension, an increase in plasma renin activity and arterial pressure is associated with increased systemic oxidative stress. When plasma renin activity later declines, PGF(2alpha)-isoprostanes remain elevated, possibly due to local activation or slow responses to angiotensin II, and may participate in sustenance of arterial pressure. Moreover, oxidation-sensitive mechanisms may influence ischemic and hypertensive parenchymal renal injury.
Asunto(s)
Hipertensión Renovascular/fisiopatología , Corteza Renal/metabolismo , Estrés Oxidativo , Animales , Presión Sanguínea , Dinoprost/análogos & derivados , Dinoprost/sangre , F2-Isoprostanos , Femenino , Depuradores de Radicales Libres/análisis , Hipertensión Renovascular/sangre , Hipertensión Renovascular/etiología , Corteza Renal/irrigación sanguínea , Obstrucción de la Arteria Renal/complicaciones , Circulación Renal , Renina/sangre , Porcinos , Sustancias Reactivas al Ácido Tiobarbitúrico/análisisRESUMEN
Hypercholesterolemia and hypertension are both risk factors for end-stage renal disease. This study was designed to examine whether their coexistence augmented impairment in renal function and redox status. Regional renal hemodynamics and function in response to vasoactive challenges with acetylcholine or sodium nitroprusside were quantified by using electron-beam computed tomography in pigs after 12 weeks of either a normal (n=10) or hypercholesterolemic (n=10) diet, renovascular hypertension (n=7), or combined hypercholesterolemia+hypertension (n=6). The hypercholesterolemic and hypercholesterolemic+hypertensive groups had significantly increased serum cholesterol levels, whereas in the hypertensive and hypercholesterolemic+hypertensive groups, mean arterial pressure was significantly elevated compared with the group fed a normal diet. Basal regional renal perfusion and glomerular filtration rates were similar among the groups. In response to acetylcholine, cortical perfusion increased in normal animals (15.6+/-4.7%, P=0.002) but not in hypercholesterolemic or hypertensive animals (8.0+/-7.4% and 8.2+/-5.9%, respectively; P>0.05). Moreover, in the hypercholesterolemic+hypertensive group, cortical perfusion response was further attenuated (2.5+/-4.8%, P=0.02) and significantly different from the group fed a normal diet (P<0.05). The response to sodium nitroprusside followed a similar pattern, and the impairment was augmented in the hypercholesterolemic+hypertensive group. The functional abnormalities in hypercholesterolemia or hypertension were associated with a decrease in systemic and/or renal tissue levels of oxygen radical scavengers that was again accentuated in hypercholesterolemia+hypertension. These results demonstrate that concurrent hypercholesterolemia and hypertension have a greater detrimental effect on renal perfusion responses compared with hypercholesterolemia or hypertension alone, associated with a marked pro-oxidant shift in redox status. These effects may potentially augment renal functional impairment and play a role in the initiation and progression of renal injury in hypertension and atherosclerosis.
Asunto(s)
Hipercolesterolemia/complicaciones , Hipertensión Renovascular/complicaciones , Riñón/fisiopatología , Acetilcolina/farmacología , Animales , Ácido Ascórbico/sangre , Colesterol/sangre , LDL-Colesterol/sangre , Depuradores de Radicales Libres/metabolismo , Hemodinámica/efectos de los fármacos , Hipercolesterolemia/sangre , Hipercolesterolemia/fisiopatología , Hipertensión Renovascular/sangre , Hipertensión Renovascular/fisiopatología , Nitroprusiato/farmacología , Oxidación-Reducción , Perfusión , Porcinos , Tomografía Computarizada por Rayos X , Resistencia Vascular/efectos de los fármacos , Vasodilatadores/farmacología , Vitamina E/sangreRESUMEN
OBJECTIVES: We intended to study the effect of hypercholesterolemia (HC) on myocardial perfusion and permeability response to increased cardiac demand. BACKGROUND: Hypercholesterolemia is associated with increased incidence of cardiac events and characterized by impaired coronary vascular function, possibly mediated partly through increased pro-oxidative conditions in plasma and tissue. However, it is yet unclear whether HC is also associated with impaired myocardial perfusion and vascular permeability responses in vivo. METHODS: For 12 weeks pigs were fed a normal, HC or HC diet supplemented daily with antioxidants (HC + AO, 100 IU/kg vitamin E and 1 g vitamin C). Myocardial perfusion and vascular permeability were measured in vivo using electron beam computed tomography before and after cardiac challenge with intravenous adenosine. Plasma and tissue oxidative status was determined ex vivo. RESULTS: Plasma cholesterol increased in all cholesterol-fed pigs but was associated with increased markers of oxidative stress only in HC pigs. Myocardial perfusion increased in response to adenosine in normal and HC + AO (+37 +/- 13% and +58 +/- 22%, respectively, p < 0.05 vs. baseline) but not in HC, whereas vascular permeability index increased only in HC pigs (+ 92 +/- 25%, p = 0.002). In HC animals, tissue endogenous oxygen radical scavengers and antioxidant vitamins were depleted and LDL oxidizability enhanced, but both were normalized in HC + AO pigs. Myocardial perfusion response was directly, and permeability inversely, associated with plasma and tissue vitamin concentrations. CONCLUSIONS: This study demonstrates that experimental HC is associated with blunted myocardial perfusion and increased vascular permeability responses in vivo to increased cardiac demand, which may be partly mediated by a shift in oxidative status.
Asunto(s)
Permeabilidad Capilar/fisiología , Enfermedad de la Arteria Coronaria/fisiopatología , Circulación Coronaria/fisiología , Depuradores de Radicales Libres/sangre , Hipercolesterolemia/fisiopatología , Estrés Oxidativo/fisiología , Animales , Dieta Aterogénica , Porcinos , Tomografía Computarizada por Rayos X , Función Ventricular Izquierda/fisiologíaRESUMEN
Hypercholesterolemia (HC) is often associated with impaired peripheral and coronary vascular responses to endothelium-dependent vasodilators, which are probably due to low bioavailability of nitric oxide. To examine the effect of HC on renal vascular and tubular function, 22 domestic pigs were studied after being fed a 12-week normal (n=11) or HC (n=11) diet. Renal regional perfusion and intratubular contrast media concentration in each nephron segment (representing fluid reabsorption) were quantified in vivo with electron-beam computed tomography before and after a suprarenal infusion of either acetylcholine (6 pigs of each diet) or sodium nitroprusside (SNP; 5 pigs of each diet). An increase in cortical perfusion, observed in normal pigs with acetylcholine (+35+/-6%, P=0. 002) and SNP (+12+/-4%, P=0.005), was blunted in the HC group (+8. 8+/-4.0, P=0.01, and -4.6+/-4.0%, P=0.1, respectively, P=0.003 and P=0.005 compared with normal) as was an increase in medullary perfusion (+58+/-21 in normal versus +24+/-11% in HC, P=0.04). A decrease in the intratubular contrast media concentration in the distal tubule and collecting duct of normal pigs was observed in all tubular segments (and was significantly enhanced in the proximal tubule and Henle's loop) in the HC group, which was associated with increased sodium excretion. The tubular and renal excretory responses to SNP were similar between the groups. In conclusion, early experimental HC in the pig attenuates renal perfusion response to both endothelium-dependent and -independent vasodilators possibly because of decreased bioavailability or decreased vascular responsiveness to nitric oxide. This vascular impairment may play a role in maladjusted renovascular responses and contribute to renal damage in later stages of atherosclerosis.
Asunto(s)
Hipercolesterolemia/fisiopatología , Riñón/fisiopatología , Circulación Renal , Vasodilatación , Acetilcolina/farmacología , Animales , Riñón/irrigación sanguínea , Pruebas de Función Renal , Nitroprusiato/farmacología , Porcinos , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
Chronic intravenous infusion of subpressor doses of angiotensin II causes blood pressure to increase progressively over the course of several days. The mechanisms underlying this response, however, are poorly understood. Because high-dose angiotensin II increases oxidative stress, and some compounds that result from the increased oxidative stress (eg, isoprostanes) produce vasoconstriction and antinatriuresis, we tested the hypothesis that a subpressor dose of angiotensin II also increases oxidative stress, as measured by 8-epi-prostaglandin F(2alpha) (isoprostanes), which may contribute to the slow pressor response to angiotensin II. To test this hypothesis, we infused angiotensin II (10 ng/kg per minute for 28 days via an osmotic pump) into 6 conscious normotensive female pigs (30 to 35 kg). We recorded mean arterial pressure continuously with a telemetry system and measured plasma isoprostanes before starting the angiotensin II infusion (baseline) and again after 28 days with an enzyme immunoassay. Angiotensin II infusion significantly increased mean arterial pressure from 121+/-4 to 153+/-7 mm Hg (P<0. 05) without altering total plasma isoprostane levels (180.0+/-24.3 versus 147.0+/-29.2 pg/mL; P=NS). However, the plasma concentrations of free isoprostanes increased significantly, from 38.3+/-5.8 to 54.7+/-10.4 pg/mL (P<0.05). These results suggest that subpressor doses of angiotensin II increase oxidative stress, as implied by the increased concentration of free isoprostanes, which accompany the elevation in mean arterial pressure elevation. Thus, isoprostane-induced vasoconstriction and antinatriuresis may contribute to the hypertension induced by the slow pressor responses of angiotensin II.
Asunto(s)
Angiotensina II/farmacología , Presión Sanguínea/efectos de los fármacos , Dinoprost/análogos & derivados , Vasoconstrictores/farmacología , Animales , Presión Sanguínea/fisiología , Dinoprost/sangre , F2-Isoprostanos , Femenino , Estrés Oxidativo , PorcinosRESUMEN
Nitric oxide (NO) synthesis inhibition with NG-nitro-L-arginine methyl ester (L-NAME) (10 micrograms.kg-1.min-1 i.v.), cyclooxygenase inhibition with meclofenamate (Meclo; 5 mg/kg i.v. bolus), and combination of drugs (L-NAME + Meclo) were used to investigate the roles of NO and prostaglandins (PG) in the hemodynamic and natriuretic responses to isotonic saline volume expansion (VE; 5% body wt over 60 min) in anesthetized dogs. Before VE, L-NAME (n = 6), Meclo (n = 6), and L-NAME + Meclo (n = 6) produced significant increments in mean arterial pressure (MAP) of 12 +/- 2, 15 +/- 3, and 17 +/- 3 mmHg, respectively. VE did not change MAP in Meclo-treated dogs, but produced a significant elevation in the control dogs (14 +/- 6 mmHg), in L-NAME-treated dogs (17 +/- 6 mmHg), and in dogs pretreated with L-NAME + Meclo (12 +/- 5 mmHg). VE alone induced marked natriuretic responses in the control (38 +/- 9 to 562 +/- 86 mumol/min), L-NAME (31 +/- 9 to 664 +/- 65 mumol/min), and Meclo groups (41 +/- 10 to 699 +/- 51 mumol/min). However, this natriuretic response was attenuated in dogs pretreated with L-NAME + Meclo (12 +/- 4 to 185 +/- 52 mumol/ min). These results indicate that 1) blockade of both NO and PGs has significant diminishing effects on volume-induced natriuresis, 2) NO blockade alone impairs volume-induced natriuresis in a manner that requires further increases in MAP to restore the natriuresis, and 3) PG blockade alone does not curtail volume-induced natriuresis.
Asunto(s)
Hemodinámica/efectos de los fármacos , Hipertensión/fisiopatología , Ácido Meclofenámico/farmacología , NG-Nitroarginina Metil Éster/farmacología , Natriuresis/efectos de los fármacos , Óxido Nítrico/fisiología , Prostaglandinas/fisiología , Solución Salina Hipertónica/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Inhibidores de la Ciclooxigenasa/farmacología , Diuresis/efectos de los fármacos , Perros , Interacciones Farmacológicas , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Hemodinámica/fisiología , Masculino , Natriuresis/fisiología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa/antagonistas & inhibidores , Circulación Renal/efectos de los fármacosRESUMEN
Advancing technology will develop lighter, less expensive, more compatible, and more reliable ambulatory blood pressure recording devices, which will result in an increased use of the procedure in clinical practice. Future longitudinal prospective studies of normotensive and hypertensive subjects may authenticate the relationship between ambulatory blood pressure values and cardiovascular morbidity and mortality, thus enabling clinicians to generate guidelines for the diagnosis and treatment of hypertension. Until that happens, ambulatory blood pressure monitoring can provide meaningful supplemental information that overcomes the limitations of office blood pressure. In addition, various cardiovascular disorders may only be evaluated by using ambulatory blood pressure monitoring. Finally, ambulatory blood pressure monitoring is valuable in determining the efficacy of antihypertensive medications and improving the research trials of these drugs.
Asunto(s)
Electrocardiografía Ambulatoria/normas , Hipertensión/diagnóstico , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Determinación de la Presión Sanguínea/normas , Ensayos Clínicos como Asunto , Electrocardiografía Ambulatoria/instrumentación , Electrocardiografía Ambulatoria/métodos , Humanos , Hipertensión/epidemiología , Hipertensión/terapia , Visita a Consultorio Médico , Pronóstico , Sensibilidad y EspecificidadRESUMEN
In the past, the diagnosis and management of hypertension has been based on office blood pressure. However, office blood pressure is not always a true reflection of a patient's blood pressure profile. Since ambulatory blood pressure monitoring permits a large number of readings to be taken in the patient's usual environment, it may provide a more representative blood pressure profile. Indeed, ambulatory blood pressure has been better correlated than office blood pressure with the target-organ complications of hypertension. Office or white-coat hypertension (elevated blood pressure only when measured in the physician's office) has been reported in 12-21% of patients in mildly hypertensive sample populations. While office blood pressure and daytime ambulatory blood pressure values are reported to be similar in normotensive subjects, ambulatory systolic and diastolic readings in hypertensive subjects have been reported as, respectively, 4-15 mmHg and 3-10 mmHg lower than office blood pressure readings. In estimating a patient's mean blood pressure and diagnosing hypertension, the greater the number of recording hours the more accurate the estimate is likely to be; in addition, increasing the number of measurements per hour also improves accuracy and increases the sensitivity of the readings. An increased frequency and severity of target-organ damage has been associated with higher 24-h blood pressure variability. Although the diagnosis of hypertension should not be based on ambulatory blood pressure alone, there are many clinical problems for which ambulatory blood pressure can be useful.